Sex is increasingly recognized as an important factor in the prevalence and severity of neuropsychiatric diseases. Notably, women are more likely than men to have depression and anxiety-related disorders, and it has been hypothesized that this sex difference results from differences in stress response systems. Dysfunctional stress responses are associated with a vast number of neuropsychiatric conditions, such as depression and post-traumatic stress disorder (PTSD). The basis for sex differences in these disorders may reside in the locus coeruleus (LC)-norepinephrine (NE) system, a major stress response system in the brain that is thought to be dysregulated in stress-related psychiatric disorders. During stress, the LC-NE system is activated by corticotropin releasing factor (CRF), a primary mediator of the stress response. At the same time endogenous opioid neuropeptides provide an inhibitory influence on LC activity that restrains CRF activation and facilitates a retun to baseline activity when the stressor is terminated. Any imbalance in the opposing regulation of the LC-NE system by CRF and opioids could influence stress-sensitivity and enhance vulnerability to stress. At the level of the LC, sex differences could be expressed through differences in sensitivity to either CRF or to endogenous opioids. Our laboratory recently characterized sex differences in CRF receptor function in the LC that render female rats more sensitive to stress. Notably, evidence from analgesic studies in both humans and rodents suggest that females are less sensitive to opiates. If this generalized to the LC-NE system, it be an additional factor contributing to increased sensitivity of the system in females to stress. Based on these observations and the important role of endogenous opioids in restraining stress-related activation of LC neurons, this research will test the hypothesis that MOR induced inhibition of the LC is attenuated in females as compared to males and this feature increases their vulnerability to stress. This research will integrate electrophysiological, biochemical and behavioral approaches and to my knowledge, will be the first set of studies focused on the neuronal effects of opiates in female rodents and the comparison to their effects in male rodents. Aim 1 will compare the LC neuronal responses to the opioid agonist, AMGO, between female and male rats. Aim 2 will determine whether repeated social stress engages endogenous opioids in the LC of female rats as has been documented in male rats. Aim 3 will use biochemical approaches to examine cellular mechanisms that could contribute to sexually distinct physiology in the LC opioid system.